Porous biocompatible implant material and method for its fabrication

ABSTRACT

A biocompatible and biodegradable implant for a cavity in a bone of a living organism is made of biocompatible and biodegradable granules. The biocompatible and biodegradable granules are provided with a coating, which includes at least one layer of a biocompatible and biodegradable polymer. The biocompatible and biodegradable implants are obtained by fusing together the polymer-coated granules through polymer-linkage of the polymer coatings of neighboring granules.

The present invention concerns a biocompatible and biodegradable implantfor implantation and/or insertion into cavities of a living organismsuch as bone defects or extraction wounds and methods for itsfabrication.

INTRODUCTION AND BACKGROUND OF THE INVENTION

Bone defects can be treated by the implantation of an autograft, anallograft, or a xenograft in the healing site. However, these biologicalimplants suffer of many drawbacks, among them, for example, shortage ofdonor tissue, bacterial and viral contamination, etc. Biocompatiblesynthetic implants generally present less osteoconductive andosteoinductive effects than biological grafts. But they are usually saveand can be manufactured in a reproducible manner.

In dental treatment, for example, the extraction of a tooth leaves anopen wound that might be contaminated by bacteria. Moreover, it is aknown problem that due to the absence of the tooth, alveolar bonespontaneously undergoes remodeling, leading to its atrophy. Such atrophymay then cause many complications for subsequent reconstruction. Inorder to prevent this process, it has been suggested in the prior art(U.S. Pat. No. 6,132,214) to implant into the extraction site abiodegradable implant, which is an exact copy of the extracted tooth.Although such implants lead to promising results, the bone in-grow inthe alveolar site is relatively low, in particular in the early stage ofthe healing process. The use of poly(α-hydroxy acids), such as, forexample polyglycolide, polylactide, or co-polymers thereof, leads to amassive release of acidic products in the environment of the implantduring its degradation. This acidification of the environment may theneven provoke tissue necrosis.

While the problems of the prior art have been described with referenceto dental problems it will be appreciated by those skilled in the artthat implants are also used as treatments for other skeleton parts. If,for example, a part of the skeleton is stricken by a tumor, the areastricken by the tumor may be removed and replaced by an implant. In thatcase with the implants known from the prior art similar problems asthose described with respect to dental treatments may arise.

Other known implant systems and methods include, for example U.S. Pat.No. 5,741,329. In this reference, it is suggested to control the changesof the pH value in the vicinity of biodegradable implants. Thus, duringthe degradation of the implant the pH value is effectively maintainedbetween 6 and 8 by incorporating a basic salt, preferably calciumcarbonate or sodium bicarbonate into a polymeric matrix, preferablypoly(lactide-co-glycolide) with a lactide to glycolide molar ratio of50/50. An amount of about 5% to about 30% of ceramic particles isdispersed in the polymer. The resultant porous implants are only poorlyinterconnected and have only poor mechanical stability.

In DE-A-31 06 445 a combination of osteoconductive bioceramics withbiodegradable polymers is proposed in order to prepare osteoconductivebiodegradable implants. Porous tricalcium phosphate ceramics areimpregnated with a therapeutically active sub stance, which is disposedin the pores of the ceramics body. For controlling the release of thetherapeutically active substance the sintered bioceramic is then coatedwith a polymer film (e.g. polydextran). In U.S. Pat. No. 4,610,692 it issuggested to impregnate a porous sintered tricalcium phosphate body withtherapeutically active substances, such as antibiotics (e.g.gentamicin). and/or disinfecting substances (e.g. polyvinyl pyrrolidoneiodine). The release of these substances is controlled by coating thesintered bioceramic porous body with a polymer film (e.g.polymethacrylate, polylactide, polydextran).

From the prior art there are already known open porous implants whichare made from an aggregation of granules. In U.S. Pat. No. 5,626,861, apolymer matrix consisting preferably of 50/50 polylactide/polyglycolidecopolymer is described, which is reinforced with particulatehydroxyapatite. This combination of materials of materials is supposedto permit to maintain the integrity of the implant as the degradationproceeds. Also the osteoconductive potential is supposedly increased. Inthe manufacture of the implant particulate hydroxyapatite having anaverage particle size of about 10-100 μm, and inert leachable particles(e.g. NaCl of a particle size of about 100-250 μm) are suspended in aPLGA solvent solution. The polymer solvent solution is emulsified andcast into any appropriate mold. As the solvent is evaporated from thesalt, ceramics and polymer mixture, the dried material retains the shapeof the mold. The salt particles within the implant are then leached outby immersion in water. By this method pores having a diameter of about100-250 μm are left in the implant. The major drawback of this method isthe necessity of a complete removal of the organic solvent, which takestime and requires costly analysis before the implant may be applied tothe patient in order to treat bone defects.

In U.S. Pat. No. 5,866,155 a method for the manufacture ofthree-dimensional macroporous polymer matrices for bone graft issuggested. For that purpose calcium phosphate based materials are addedto polymer microspheres in order to produce flexible matrices for bonereplacement or tissue engineering. In one embodiment a sinteredmicrosphere matrice is prepared. A mixture containing degradable polymermicrospheres, calcium phosphate based materials and porogen particles(NaCl) is cast in a mold, compressed and sintered such, that themicrospheres of the cast mixture bond to each other after heating overtheir glass transition temperature. After removal from the mold andcooling, the porogen is leached out in order to produce a matrice foruse in bone replacement. In a second embodiment it is described that themicrospheres a bonded together by using an organic solvent. Afterremoval of the solvent and leaching out of the porogen materialthree-dimensional structures are obtained for bone replacement. A stillfurther alternative method consists in the preparation of gel-likepolymer microspheres, having sticky surfaces. Calcium-phosphateparticles are then added to the sticky microspheres. The mixture isstirred, cast in a mold and dried in order to obtain the desired openporous structure.

Lu et al. in “3D Porous Polymer Bioactive Glass Composite PromotesCollagen Synthesis and Mineralization of Human Osteoblast-like Cells”,Sixth World Biomaterials Congress Transactions, Hawaii, (2000), p: 972describe a method to prepare 3-D constructs made of Bioglass® 45S5 andpoly(lactide-co-glycolide). The method consists of the dissolution ofthe polymer in a methylene chloride and the addition of Bioglassgranules having a size of less than 40 μm, to the solution. The mixtureis then poured into a 1% polyvinyl alcohol solution and the spheres areallowed to harden. 3-D constructs are made by heating the microspheresin a mold at 70° C. for 20 hours. The method suffers the disadvantagethat it is very difficult to control the degree of deposition of thepolymer on the surface of the bioglass granules. An aggregation of thegranules is also difficult to avoid. A heat treatment of the granulesgenerally leads to problems, in particular if highly volatile and/orthermolabile biologically active substances, such as, for example,growth factors, are to be added to the granules.

In U.S. Pat. No. 6,203,574 it is suggested to bond ceramic granules witheach other using a biodegradable substance. By the suggested method aninterconnecting open porous structure is supposed to be obtained.Hydroxyapatite particles of sizes from 100-300 μm are heated to 200° C.,while polylactide particles having a particle size smaller than 210 μmare heated to 100° C. The hydroxyapatite particles are then added to thepolylactide particles. The mixture is intimately shaken in order toobtain a homogeneous mixture of particles. By this method thepolylactide adheres to the surface of the hydroxyapatite particles.Thereafter, a mixture of polylactide particles containing finehydroxyapatite and polylactide granules with a size of 210-420 μm isadded to the coated large hydroxyapatite particles. The resultingmixture is poured into a mold and heated to 195° C. After cooling amolded open porous implant is obtained. However, this method suffers anumber of drawback. The particles are bonded together in a heatingprocess, which excludes the incorporation of thermally labileosteoinductive substances such as growth factors or other proteins.Antibiotics can also be altered and even destroyed by the necessaryelevated temperatures. Although the polylactide particles are supposedto adhere to the surface of the ceramic particles they can also adhereto each other. Thus, aggregates of polylactide are formed. This can leadto the formation of inhomogeneous implants. The suggested method doesnot allow the control of the thickness and homogeneity of the coating ofthe ceramic particles. Thus, the suggested system may not be optimal fora controlled delivery of pharmaceutically active substances. Moreover,the suggested method is incompatible with the desire to use as littlepolylactide as possible for the production of implants.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide a biocompatible andbiodegradable implant, which overcomes the aforementioned problemsassociated with materials and methods of implantation and/or insertioninto bone cavities or extraction wounds. A biocompatible andbiodegradable implant is to be provided which uponinsertion/implantation assists in the reduction of a loss of bonevolume. It is a further object of the present invention to provide animplant which may be assembled and shaped easily in the desired mannerto a defect-analogous implant in order to avoid hollow spaces betweenthe implant and the sidewalls of the cavity. There is to be provided animplant having an open interconnected macro porosity, which allowstissue in-growth. The properties of the biocompatible implant shall besuch, that it also may be used for reduction of bacterial growth andinfection in a bone wound and the like. It is still a further object ofthe invention to provide a method for a fast and comparably simple andcost effective fabrication of the biocompatible and biodegradableimplant according to the invention.

According to the invention a biocompatible and biodegradable implant forthe filling of a cavity in a living organism such as, for example, abone defect, is suggested which is made of a number of biocompatible andbiodegradable granules made of materials selected from the groupconsisting of biopolymers, bioglasses, bioceramics preferably calciumsulfate, calcium phosphate such as monocalcium phosphate monohydrate,monocalcium phosphate anhydrous, dicalcium phosphate dihydrate,dicalcium phosphate anhydrous, tetracalcium phosphate, calciumorthophosphate phosphate, α-tricalcium phosphate, β-tricalciumphosphate, apatite such as hydroxyapatite, or a mixture thereof. Thebiocompatible and biodegradable granules are provided with a coating,which comprises at least one layer of a biocompatible and biodegradablepolymer. The biocompatible and biodegradable polymer-coating is selectedfrom the group consisting of poly(α-hydroxyesters), poly(orthoesters),polyanhydrides, poly(phosphazenes), poly(propylene fumarate), poly(esteramides), poly(ethylene fumarate), polylactide, polyglycolide,polycaprolactone, poly(glycolide-co-trimethylene carbonate),polydioxanone, co-polymers thereof or blend of those polymers. Thebiocompatible and biodegradable implants are obtained by fusing togetherthe polymer-coated granules through polymer-linkage of the polymercoatings of neighboring granules.

By special selection of the biocompatible and biodegradable materialsfor the granules and their coatings, the growth and the proliferation ofosteoblast-like cells may be supported during the degradation of theimplant, which is finally replaced by newly formed bone tissue. Theimplant may in certain cases also prevent the erosion of the bone tissuesurrounding the bone defect to be healed.

The fusing process is carried out such, that implants having an openinterconnected porosity with macropores having average diameter fromabout 100 μm to about 500 μm, preferably about 200 μm to about 300 μm isachieved.

The fusing of the polymer-coated granules to a biocompatible andbiodegradable implant is carried out with biocompatible andbiodegradable granules having micropores with average diameters of aboutlarger than 0 to about 10 μm. The employed process is selected such,that in the implant the microporosity remains and/or macropores areformed having average diameters of about more than 10 μm to about 500μm, preferably about 100 μm to about 300 μm.

It is to be noted that only the uncoated biocompatible and biodegradablegranules have the claimed porosity; once the granules are coated theporosity is practically not recognizable any more from the outside.Granules made of bioceramics, which have been sintered very densely, donot have a considerable microporosity at all. The porosity of thegranular material and/or the implants provides an even larger surfacearea. In addition the pores may be filled, e.g., with an antibioticsubstance, with growth factors and like biologically active substances.Thus, the biocompatible and biodegradable implants, when implanted intoa cavity or extraction wound not only fill the cavity, but permit thecontrolled release of biologically active substances. For example, thesubstance within the pores may be selected such that bacterial growth,fungal growth and the like more are hindered.

Preferably granules are selected, which have an equivalent-diameter ofabout 350 μm to about 2000 μm, preferably 500 μm to 1000 μm. Granules ofthe selected equivalent diameters are easily handled and readily furtherprocessed.

While the term equivalent-diameter indicates that the biocompatible andbiodegradable granules may be of irregular shape, it is of advantagewhen it is provided with a regular shape. Preferably it has a generallyspherical shape. Due to its homogeneous structure the spherical shape ofthe granular material allows a better handling and an easier estimationof the required quantity of granular material in order to fill a knownvolume of a cavity.

The biocompatible and biodegradable granules are preferably formed froma powdery base material, said powdery base material having an equivalentdiameter of about 0.1 μm-about 10 μm and granules being formed by anadditive granulation in a granulator. This method for forming granulesis well approved and allows a reproducible formation of granularmaterial having the desired equivalent diameters with only smalldeviating fractions.

In an alternative embodiment of the invention the biocompatible andbiodegradable granules may be hollow instead of being solid granules.The use of hollow granules reduces the amount of implanted material andallows a better in situ integration. In a further advantageousembodiment, the granules may comprise at least opening in the wallenclosing the interior hollow space, which opening in the wall is largerthan micropores in the wall, and being preferably of macroscopic size.By providing the hollow biocompatible and biodegradable granules with anopening in the granule wall the possibility of a tissue in-growth intothe biocompatible and biodegradable implants is enhanced. The hole withan opening in the granule wall may be produced from slurry consisting ofthe biocompatible material, water and an adhesive (Wintermantel et al.1996). Droplets of the slurry are brought onto a heated plate. The waterin the slurry droplet boils and evaporates instantaneously out of thedroplets leaving an evaporation crater in the droplet wall. When thedroplets are cooled off, hollow granules having an opening in thegranule wall are formed.

The biocompatible and biodegradable coating has a thickness of 2 μm to300 μm, preferably about 5 μm to about 20 μm. The mechanical stabilityof an implant made of coated granules depends on the thickness and thehomogeneity of the coating. By an insufficient coating thickness thegranules cannot stick together in the required extent. On the otherhand, large amounts of coating materials can lead to the decrease of thepH-value below pH 7.4 in the vicinity of the implant during itsdegradation. Therefore, the optimal thickness of the biocompatiblecoating is a result of a compromise between implant stability and theamount of material, which will degrade. The preferred coating thicknessof the granules may also be expressed as a weight fraction of about 4%to about 15% coating materials of the total weight of the implant. Thebiocompatible coating is made of a biodegradable polymer. Thus, it isensured, that after a specified and defined time period the coatedgranular material may degrade or be resorbed or dissolve within thecavity without any residues.

The coating of the biocompatible and biodegradable granules may compriseone or more layers of varying average thickness. At least the outmostcoating layer is made of a biodegradable material. This embodiment ofthe invention allows providing the biocompatible and biodegradablegranules with several coatings for specific purposes. The outmostbiodegradable coating may be selected in accordance with a certaindesired delay in degradability. Thus, the coating layer underneath isonly exposed after a certain desired time period has expired. This, forexample, allows a retarded delivery of a bioactive substance. Thus, thebiocompatible and biodegradable granules may be coated with differentcoatings, which each is biodegradable and displays a specific effect.

In a further embodiment of the invention a biologically active substanceis integrated into the biocompatible and biodegradable granules and/orinto the coating, and/or forming a coating layer itself. Thus, acontrolled delivery of the biologically active substance is enabled. Theamount of the biologically active substance may easily be defined bycontrolling the coating process, for example. By integratingbiologically active substance into a submerged coating layer or into thegranular material itself, a controlled retarded release of thebiologically active substance may be accomplished.

The biocompatible and biodegradable implants are easily formed frombiocompatible and biodegradable granules. This implant comprises anumber of coated biocompatible and biodegradable granules and may beshaped in any required manner. Thus, the biocompatible and biodegradablegranules form the prerequisites for temporary implants, which may veryeasily be shaped to form an exact match of a freshly created cavity orextraction wound. The porosity of the implants is well controllable bythe applied method for fusing of the granules. The coated granules areselected from solid granules, porous granules, hollow granules, hollowgranules with at least one opening in the granule wall, or mixturesthereof.

It may be advantageous to provide a biocompatible and biodegradableimplants, which comprises in addition non-coated biocompatible granulesmade of a biocompatible and biodegradable material selected from thegroup consisting of one of biopolymers, bioglasses, bioceramicspreferably calcium sulfate, calcium phosphate such as monocalciumphosphate monohydrate, monocalcium phosphate anhydrous, dicalciumphosphate dihydrate, dicalcium phosphate anhydrous, tetracalciumphosphate, calcium orthophosphate phosphate, α-tricalcium phosphate,β-tricalcium phosphate, apatite such as hydroxyapatite, or a mixturethereof, and said granules being free from any coatings and selectedfrom solid granules, porous granules, hollow granules, hollow granuleswith at least one opening in the granule wall, and mixtures thereof. Thecoated and uncoated granules are thoroughly mixed such, that they aresafely fused together by the preferred method of production and stillhare the required stability. By providing a mixture of coated andnon-coated granules for the prod of the biocompatible and biodegradableimplants, the amount of coating materials, which must degrade, may befurther reduced.

The biocompatible and biodegradable implant may consist of one type ofbiocompatible and biodegradable granules only. In a preferred embodimentof the invention, the biocompatible and biodegradable implant is made oftwo or more kinds of coated granules. The term different includesbiocompatible and biodegradable granules having different sizes. Thecoated granules are distinct from each other and may consist ofdifferent biocompatible materials and/or comprise polymer-coatings,which are distinct from each other. Thus, an implant may be “designed”not only as an ideal match for a bone cavity or an extraction wound butalso in accordance with further specific requirements, such as, forexample, stability, resorbability and/or solubility of the implant.

In a preferred embodiment the biocompatible and biodegradable implant isobtained from biocompatible and biodegradable granules which are fusedtogether within a mold in a pressurized CO₂ atmosphere. The CO₂atmosphere acts as a slight solvent with respect to the polymer-coatedgranules and enhances the linkage of the granules with each other. Theproduced biocompatible and biodegradable implants preferably comprisemacropores in between the fused together granules. The macropores may beinterconnected and have average sizes from about 100 μm to about 500 μm,preferably about 200 μm to about 300 μm. The macropores serve to enhancethe in-growth of tissue into the implant and thus allow a fasterregeneration of the healing site.

A preferred field of use for the biocompatible and biodegradable implantaccording to the invention is the use as a temporary replacement for anextracted tooth root or the like. Fusing of the individualpolymer-coated granules to a making implant may be accomplished veryeasily and very fast on-site from prefabricated biocompatible andbiodegradable granules.

The biocompatible and biodegradable granules may be spray-coated,preferably in a fluid bed machine, or immersion-coated with the desiredbiocompatible polymer(s). Both methods lead to the biocompatible andbiodegradable granules having the required properties. The spray coatingprocess in a fluid bed machine is preferred though, because it allowsthe fabrication of a great number of practically identicalpolymer-coated biocompatible and biodegradable granules in a very fastand economic manner. The technique is well proven and allows an easycontrol of the thickness of the coating layer(s) and the fabrication ofbiocompatible and biodegradable granules having multiple coating layers,which are distinct from each other. The coating in fluidized bed machineresults in a homogenous and continuous coating, which offers a barrieragainst bacterial contamination of the granules or of implants madetherefrom. During the coating process, the granules do not adhere toeach other, thus avoiding the formation of undesirable aggregates whichmight lead to highly inhomogeneous size distributions and coatingthickness. The coated granules retain their excellent free-flowproperties, which is necessary for an eventual further processing. Dueto the homogeneity of the coating only a low amount of coating material,in particular PLGA, is required for the further consolidation of animplant. Thus, the risks of inflammation or tissue necrosis due to amassive release of acidic products in the environment of an implantduring its degradation are significantly reduced. An integration ofbiologically active substances into the coating film(s) may be wellcontrolled by the coating in a fluid bed machine. Thus, each granules isloaded with the same amount of the biologically active substance. Thethickness of the coating is well controlled in the process. Therefore,even the release of an integrated biologically active substance ispredictable and well controlled.

Biocompatible and biodegradable implants are made from coated granulesof a biocompatible and biodegradable material. They may also compriseuncoated granules. The granules are preferably fused together in a moldhaving a cavity corresponding to the required shape. After removal fromthe mold the implants need not be finished but may be directly insertedinto a bone cavity or an extraction wound. However, due to therelatively high stability of the implants, they may even be furtherfinished, such as, for example, by cutting away portions of the implant,if the need arises.

The fusing together of the biocompatible and biodegradable granules mayalso be accomplished by heat treatment, or by exposure to a solvent. Theselected method depends on the type of coating and may employ evencombinations of the different kinds of mechanical, physical and chemicalprocesses. In a method the biocompatible and biodegradable granules arefused together within a mold having the desired mold cavity bysubjecting them to a pressurized CO₂ atmosphere for a time span of atleast about 3 seconds, typically about 3 seconds to about 180 seconds.The CO₂ atmosphere acts as a slight solvent with respect to thepolymer-coated granules and enhances the linkage of the granules witheach other. The pressure of the CO₂ atmosphere ranges from about 20 barto about 200 bar, preferably about 50 bar. At these pressures a reliablebondage of the granules to each other is achieved while at the same timeavoiding a damage of the individual biocompatible and biodegradablegranules. The bonding of the granules in a CO₂ atmosphere has theadvantage that the produced biocompatible and biodegradable implant doesnot require any purification step prior to implantation.

In an alternative method the fusing together of the biocompatible andbiodegradable granules is accomplished by heat treatment. The fusion ofthe coated granules is achieved at elevated temperatures of about 70° C.to about 220° C., preferably about 75° C. to about 90° C. The heattreatment lasts for a time span of at least about 10 seconds, typicallyabout 10 seconds to about 5 minutes.

The incorporation of growth factors into a biocompatible andbiodegradable implant can also be achieved very simply by mixing loadedmicrospheres with the biocompatible and biodegradable coated granules.This allows manufacturing the coated granules under non-asepticconditions with subsequent sterilization, while the microspheres, whichcarry the growth factors, are produced under aseptic conditions. Themixing of the coated granules and the microspheres is done just beforethe preparation of the biocompatible and biodegradable implant. Thebonding is achieved in a gaseous CO₂ atmosphere at low temperatures ofabout 20° C. to about 37° C. and a pressure of about 20 bar to about 200bar, preferably about 30 bar to about 40 bar. Under these conditions andat such low temperatures, the growth factors may be handled easilywithout the danger of degradation or alteration.

BRIEF DESCRIPTION OF THE DRAWINGS

Further advantages of the invention will become apparent from thedescription of exemplary embodiments of the invention in which:

FIG. 1 is an electron microscope view of a biocompatible andbiodegradable coated granule used for the fabrication of implantsaccording to the invention;

FIG. 2 is a detail of a cross-sectional view of the coated biocompatibleand biodegradable granule and of FIG. 1 showing the homogeneous and thincoating of a microporous granule;

FIG. 3 is an electron microscope view of a hollow granule having amacroscopic opening in the granule wall; and

FIG. 4 is a light microscope cross-sectional view of a biocompatible andbiodegradable implant made of a number of coated solid biocompatible andbiodegradable granules demonstrating the interconnected and openporosity in between the granules.

DETAILED DESCRIPTION OF THE INVENTION

The coated granule 1 depicted in FIGS. 1 and 2 is of generally sphericalshape. In spite of its usually relatively porous structure it has a verysmooth outer surface due to being coated with a biocompatible andbiodegradable polymer 3. The base 2 material in the shown embodiment istricalcium phosphate (TCP). From FIG. 2, it is apparent that the granule1 has a porous structure preferably comprising micropores having anaverage diameter of larger than 0 μm to about 10 μm, preferably about0.1 μm to about 6 μm. It is to be noted that very densely sinteredgranules may have no microporosity at all. The coating 3 is apoly-lactide-co-glycolide (PLGA) and encloses the base material 2completely like a shell. It has a thickness of about 2 μm to about 300μm, preferably about 5 μm to about 20 μm.

FIG. 3 shows a hollow, generally spherical granule 11. The wall 13 ofthe granule 11 has an opening 14, which communicates with the cavity 12of the granule. The hollow spherical granules 11 with an opening 14 inthe granule wall 13 may be produced from slurry consisting of thebiocompatible material water and an adhesive. Droplets of the slurry arebrought onto a heated plate. The water in the slurry droplet boils andevaporates instantaneously out of the droplets leaving an evaporationcrater in the droplet wall. When the droplets are cooled off hollowgranules 11 having a macroscopic opening 14 in the granule wall 13 areformed. This granule may then be coated.

FIG. 4 shows a light microscopy image of a cross-section of a TCP-PLGAimplant 4 made of a number of granules 1 as depicted in FIGS. 1 and 2.The implant may also be formed of hollow granules, or of hollow granules11 having an opening in the granule wall 13, as depicted in FIG. 3, orof mixtures thereof. The granules may all be coated or be only partlycoated. The polymer coating cannot be observed at the shownmagnification. The interconnected macroscopic porosity, however, candearly be observed. The binary image of FIG. 4 is achieved afterdigitizing the image values, noise reduction and thresholding of theresults. The granules 1 are fused with each other, the fusing havingbeen achieved within a mold in a pressurized CO₂-atmosphere. Theindividual granules 1 are fused together only by linkage of thepolymer-coatings of the granules. The shape of the individual granules 1is basically spherical. The depicted implant 4 is made of biocompatibleand biodegradable granules 1 of different sizes in the range of about500 μm to about 800 μm, which results in an open interconnectedstructure with a good resistance to mechanical stress, such as, forexample, pressure.

Granular Base Material:

Preferred biodegradable or bioresorbable materials include bioceramicssuch as calcium phosphates and calcium sulfates, bioglasses, andmixtures thereof. The calcium-based ceramics include, as monocalciumphosphate monohydrate (MCPM, Ca(H₂PO₄)₂.H₂O), monocalcium phosphateanhydrous (MCPA, Ca(H₂PO₄)₂), tetracalcium phosphate (TetCP,Ca₄(PO₄)₂O), calcium orthophosphate phosphate (OCP, Ca₈H₂(PO₄)₆.5H₂O),calcium pyrophosphate (CaP, Ca₂P₂O₇), dicalcium phosphate anhydrous(DCP, CaHPO₄), dicalcium phosphate dihydrate (DCPD, CaHPO₄.2H₂O),β-tricalcium phosphate (β-TCP, Ca₃(PO₄)₂), α-tricalcium phosphate(α-TCP, Ca₃(PO₄)₂), and apatite such as hydroxyapatite (HA,Ca₁₀(PO₄)₆(OH)₂). Calcium phosphate ceramics are known for theirexcellent biocompatibility and are therefore used in various biomedicalapplications, HA and TCP among them being the most used bioceramics inorthopedic and maxillo-facial applications and for the treatment of bonedefects. Their dose ionic similarity with the mineral components ofbone, their adjustable resorption kinetics to the need of a specifictherapy and their bioactive properties have been mentioned before in theprior art. While HA is commonly considered to be non-biodegradable, someresorption behavior has been reported in in-vivo studies (Oonishi et al.1999). β-TCP is generally considered to be biodegradable and is known todegrade faster than HA. After resorption of TCP in vivo new bone tissueis reported to replace the resorbed materials.

Preparation of β-TCP Granules

From β-TCP powder granules are prepared, for example, by aspheronization route. 70 g β-TCP powder (purum p.a. >96%, Fluka, CH) ismixed with 1 g dextin (Retalin Dextrin K51) in a mortar. 20 ml deionizedwater is slowly added to the powdery mixture under continuous stirring.The resultant paste is extruded through a multi-hole (φ: 800 μm) nozzle(Cyclo, Typ XYCG, Probst Technik, CH) and spheronized during ca. 3 min apelletrounder (Probst Technik, CH) in order to obtain granules having anaverage diameter of about 350 μm to about 1000 μm. The obtained β-TCPgranules with a diameter between 500 and 1000 μm are then calcinated andsintered at a temperature of 1150° C. during 4 hours in a furnace(Nabertherm, CH).

Other method such as high-shear mixer and fluidized bed granulation canalso be used in order to produce rounded granules.

Biocompatible and Biodegradable Polymer-Coating

Meanwhile a large number of biocompatible and biodegradable orbioresorbable polymers are known from the prior art, amongpoly(α-hydroxyesters), poly(ortho esters), polyanhydrides,poly(phosphazenes), poly(propylene fumarate), poly(ester amides),poly(ethylene fumarate), polylactide, polyglycolide, polycaprolactone,poly(glycolide-co-trimethylene carbonate), polydioxanone, co-polymersthereof and blend of those polymers. By way of example only theinvention will be illustrated with reference topoly-lactide-co-glycolide (PLGA), which is known for itsbiocompatibility and biodegradability. For this purpose, a solution ofPLGA with a lactide to glycolide molar ratio of 50/50 (PLGA 50:50,Resomer RG503, Boehringer Ingelheim, D) in dichloromethan (CH₂Cl₂) isfirst prepared. The concentration of the polymer was about 0.1 g to 0.2g PLGA 50:50 in 1 ml CH₂Cl₂. The β-TCP granules are immersed in the PLGA50:50 solution. While the resultant mixture is constantly stirred, thesolvent evaporates until a thin film of polymer is deposed on thesurface of the β-TCP granules. Agglomerated granules can be thenseparated using a labor mixer and sieved. The extraction of the solventis finally carried out for 36 h under vacuum (100 mbar).

A far more economic coating method, which results in a very homogenouscoating of the β-TCP granules is the spray coating process in afluidized bed machine (GPCG1, Glatt, D). For that purpose, 310 g pureβ-TCP granules (500-710 μm) are placed on a perforated plate. While airflows through the plate, the granules are fluidized. A cylinder, whichmay be placed in the center above the perforated plate, canalizes thefluidized granules due to a flow gradient, which exists between thecenter of the plate and the circumference thereof. In this case, a spraynozzle is located underneath the cylinder in the center thereof. As thegranules are fluidized and flow up the cylinder, they are coated with a7.5% w/w PLGA 50:50 (Resomer RG503, Boehringer Ingelheim, D) in CH₂CL₂solution. Due to the continuous circulation of the fluidized granules avery homogeneous coating is obtained. After spraying 570 g PLGA50:50solution at a spraying rate of ca. 10 g/min, the coating process isstopped. With these coating parameters, granules can be obtained with acoating layer corresponding to about 6% of the total weight of thegranules. The coated granules are then taken out of the fluidized bedmachine and dried under vacuum (100 mbar) during at least 24 hours.

Using the same fluidized bed machine, it is also possible to coat β-TCPgranules with PLGA85:15. (Resomer RG858, Boehringer Ingelheim, D). Inone experiment, 493 g β-TCP granules (500-710 μm) were coated with ca.1300 PLGA85:15 in CH₂Cl₂ solution. At the end of the coating, coatedgranules with ca. 13% w/w PLGA85:15 could be obtained.

It is apparent for those skilled in the art that by selecting differentcoating solutions and varying the coating time, different layers ofcoatings having different thicknesses may be applied to the β-TCPgranules. This includes the coating with biologically active substancesas an individual coating or mixed or dissolved in the polymer coating.

Preparation of Biocompatible and Biodegradable Implants

β-TCP-PLGA biocompatible and biodegradable implants are prepared fromβ-TCP granules, which are coated with at least one layer of PLGA.Various methods for the fabrication of implants may be used in order tofuse the polymer-coated granules together, among them heat treatments,application of solvents, use of pressurized CO₂, chemical linkage,mechanical fusion by applying pressure, and mixtures of those methods.

By a fusion method, which applies a heat treatment at moderatetemperatures the biocompatible and biodegradable implant may be preparedas follows:

700 mg PLGA 50:50 coated β-TCP granules are poured into a polysiloxanemold, having the desired shape, and heated to a temperature of about 75°C. to about 90° C. The granules are slightly compressed in the mold andkept at 75° C. to about 90° C. for at least about 10 seconds. Typicallythe process time amounts to about 10 seconds to about 5 minutes,preferably for about 1 minute to about 2 minutes. After that, the moldcontaining the fused granules is cooled down to ambient temperature.After cooling, the polymer coating hardens and the implant becomesstable enough to be removed from the mold and implanted.

The fusing of coated granules applying a method using pressurized CO₂may be carried out as follows:

After filing a polysiloxane mold with a desired shape with 700 mg PLGA50:50 coated β-TCP granules, the mold is place in a high pressure vesselat room temperature. After closure of the vessel, CO₂ is introduced intothe vessel until a pressure of about 50 bar is reached. The pressure isincreased at a ramp of about 2 bar per second. Once the maximum pressureis reached, it is held for at least about 3 seconds. Typically thepressure is held for about 3 seconds to about 180 seconds, preferablyless than 30 seconds. Then, the CO₂ pressure is decreased at a rate ofabout 0.5 bar per second. As the CO₂ pressure in the vessel equilibrateswith the outer atmospheric pressure, the vessel is opened and the moldis taken out. The implant made of the fused coated granules can then beextracted out of the mold. The whole process is preferably performed atroom temperature or at slightly elevated temperatures of about 24° C. toabout 37° C. Such an implant has a porosity of ca. 55% and a median porediameter of ca. 280 μm.

Since the β-TCP granules are homogeneously coated with PLGA they arecapable of fusing together during the CO₂ treatment. The CO₂ acts as asolvent for the coating. This results in a decrease of the glasstransition temperature (T_(g)) of the polymer below the processingtemperature. By the combination of the gas pressure and the reduction ofT_(g) the granules are able to fuse by polymer linkage only. Thus, it isapparent that homogenous coating of the granular base material is anessential prerequisite for the fusing of the coated granules. Theimplants comprise interstitial spaces in between the fused granules. Thesize of the interstitial spaces is depending on the thickness of thecoating, on the compaction of the implant, and on the size of the coatedgranules. Thus, an application of moderate additional pressure on themold cavity during the fusing of the granules reduces the interstitialspace and allows a control thereof. An implant having largerinterstitial spaces may be desirable in order to provide room for thein-growth of newly formed tissue.

Preparation of Biocompatible and Biodegradable Implants Loaded withBiologically Active Substances

The processing using pressurized CO₂ for the fusing of the granules ispreferred, because it permits to produce biocompatible and biodegradableimplants including, for example, PLGA microspheres loaded withbiologically active substances such as insulin like growth factor-1(IGF-1).

The preparation of biocompatible and biodegradable implants loaded withIGF-1 could be carried out as follows:

25 mg PLGA50:50 microspheres (Resomer RG502H, Boehringer Ingelheim, D)loaded with IGF-1 were mixed in a polysiloxane mould with 950 mg ofcoated granules using a small spatula. The granules used for thisexperiment were coated with PLGA50:50 (Resomer RG502H, BoehringerIngelheim, D) in order to achieve a material compatible interfacebetween the granules and the microspheres. For a homogenous microspheredistribution through the scaffold, the polysiloxane mould filled withthe biomaterials was vibrated with a vortex device (level 3, VortexGenie 2, Bender & Hobein, CH) during 20 s. In order to prevent thesegregation of the microspheres on the bottom of the mould, the mouldwas turned upside down and the vibrating was repeated. The consolidationof the implant was then achieved under pressurized CO₂ atmosphere at 30bar during 60 s. After the consolidation step, the biocompatible andbiodegradable implant loaded with IGF-1 could be extracted out from themould and analyzed.

The release kinetics of IGF-1 was investigated for microspheres loadedwith this biologically active substance and for implants containing suchloaded microspheres and consolidated using the pressurized CO₂technique. It appeared that after 1 day, the released amount of IGF-1from the microspheres was ca. 40% and the released amount from thebiocompatible and the biodegradable implant was ca. 13%. At day 7, thereleased amount of IGF-1 from the microspheres was ca. 100% and theamount from the implant was ca. 80%. After about 20 days, the amount ofIGF-1 was totally released from the biocompatible and biodegradableimplant. This demonstrates that such implants could be used as a drugdelivery system for the treatment of bone defects.

In accordance with the invention there is described a biocompatible andbiodegradable implant for a cavity in a bone of a living organism whichis made of a biocompatible and biodegradable granules which are selectedfrom the group consisting of biopolymers, bioglasses, bioceramicspreferably calcium sulfate, calcium phosphate such as monocalciumphosphate monohydrate, monocalcium phosphate anhydrous, dicalciumphosphate dihydrate, dicalcium phosphate anhydrous, tetracalciumphosphate, calcium orthophosphate phosphate, α-tricalcium phosphate,β-tricalcium phosphate, apatite such as hydroxyapatite, or a mixturethereof. The biocompatible and biodegradable granules are provided witha coating, which comprises at least one layer of a biocompatible andbiodegradable polymer which is selected from the group consisting ofpoly(α-hydroxyesters), poly(orthoesters), polyanhydrides,poly(phosphazenes), poly(propylene fumarate), poly(ester amides),poly(ethylene fumarate), polylactide, polyglycolide, polycaprolactone,poly(glycolide-co-trimethylene carbonate), polydioxanone, co-polymersthereof and blends of those polymers. The biocompatible andbiodegradable implants are obtained by fusing together thepolymer-coated granules through polymer-linkage of the polymer coatingsof neighboring granules.

The invention claimed is:
 1. Biocompatible and biodegradable implant forfilling a cavity in a living organism comprising polymer-coatedbiocompatible and biodegradable granules fused together through polymerlinkage, said granules being made of biocompatible and biodegradablematerials selected from the group consisting of biopolymers, bioglasses,bioceramics and a mixture thereof, and said granules having anequivalent-diameter in a range from about 350 μm to about 2000 μm; amajor portion of the surface area of said granules being coated with atleast one biocompatible and biodegradable layer of a polymer selectedfrom the group consisting of poly(α-hydroxyesters), poly(ortho esters),polyanhydrides, poly(phosphazenes), polypropylene fumarate), polyesteramides), polyethylene fumarate), polylactide, polyglycolide,polycaprolactone, poly(glycolide-co-trimethylene carbonate),polydioxanone, co-polymers thereof and a blend of the polymers, and saidpolymer layer having a thickness in a range of 2 μm to 300 μmcorresponding to a weight fraction of about 4% to about 15% of theweight of said implant, wherein the polymer linkage is carried out suchthat after fusing the granules together, an open interconnected porositywith macropores having an average diameter in a range of about 100 μm toabout 500 μm, is achieved.
 2. Biocompatible and biodegradable implant asin claim 1, wherein the bioceramic is calcium sulfate or calciumphosphate.
 3. Biocompatible and biodegradable implant as in claim 2,wherein the calcium phosphate is selected from the group consisting ofmonocalcium phosphate monohydrate, monocalcium phosphate anhydrous,dicalcium phosphate dehydrate, dicalcium phosphate anhydrous,tetracalcium phosphate, calcium orthophosphate phosphate, calciumpyrophosphate, α-tricalcium phosphate, β-tricalcium phosphate, apatite,hydroxyapatite and a mixture thereof.
 4. Biocompatible and biodegradableimplant as in claim 1, wherein the equivalent-diameter of said granulesis in the range of about 500 μm to about 1000 μm.
 5. Biocompatible andbiodegradable implant as in claim 1, wherein said granules are of aregular shape.
 6. Biocompatible and biodegradable implant as in claim 5,wherein said regular shape is a spherical shape.
 7. Biocompatible andbiodegradable implant as in claim 1, wherein the thickness of thepolymer layer is in the range of about 5 μm to about 20 μm. 8.Biocompatible and biodegradable implant as in claim 1, wherein theaverage diameter of the macropores is in the range of about 200 μm toabout 300 μm.
 9. Biocompatible and biodegradable implant as in claim 1,wherein the biocompatible and biodegradable granules are selected fromthe group consisting of solid granules, porous granules, hollowgranules, hollow granules with at least one opening in the granule wallenclosing the interior hollow space, and mixtures thereof. 10.Biocompatible and biodegradable implant as in claim 9, wherein porousbiocompatible and biodegradable granules are used.
 11. Biocompatible andbiodegradable implant as in claim 10, wherein the porous biocompatibleand biodegradable granules include micropores having an average diameterin a range of more than 0 to about 10 μm.
 12. Biocompatible andbiodegradable implant as in claim 11, wherein the opening in the granulewall of the hollow granules is larger than the average diameter of themicropores in the porous granules.
 13. Biocompatible and biodegradableimplant as in claim 12, wherein the average diameter of the microporesis in the range of about 0.1 μm to about 6 μm.
 14. Biocompatible andbiodegradable implant as in claim 11, wherein the porous granulesinclude macropores having an average diameter in a range of more thanabout 10 μm to about 500 μm.
 15. Biocompatible and biodegradable implantas in claim 14, wherein the average diameter of the macropores is in therange of about 100 μm to about 300 μm.
 16. Biocompatible andbiodegradable implant as in claim 1, further comprising at least onebiological active substance that is integrated into the granules and/orinto the biocompatible and biodegradable coating, and/or forming acoating layer itself.
 17. Biocompatible and biodegradable implant as inclaim 1, wherein mixtures of non-coated and polymer-coated granules arefused together.
 18. Biocompatible and biodegradable implant as in claim1, wherein said biodegradable and biocompatible implant is made of twoor more kinds of granules, said two or more kinds of granules being madeof different biocompatible materials and/or comprising polymer-coatingsthat are distinct from each other and/or having different equivalentdiameters.
 19. Biocompatible and biodegradable implant as in claim 18,wherein the two or more kinds of granules are solid granules, porousgranules, hollow granules, and/or hollow granules with at least oneopening in the granule wall, or mixtures thereof, and said implant beingshaped in a manner to accommodate the granules.
 20. Biocompatible andbiodegradable implant as in claim 1, wherein the granules are mixed withmicrospheres made of a biodegradable and biocompatible material andloaded with at least one biologically active substance. 21.Biocompatible and biodegradable implant as in claim 1, wherein saidbiocompatible and biodegradable granules are spray-coated with abiocompatible and biodegradable polymer to form a polymer coating. 22.Biocompatible and biodegradable implant as in claim 21, wherein saidbiocompatible and biodegradable granules are spray-coated in a fluidizedbed machine.
 23. Biocompatible and biodegradable implant as in claim 21,wherein the thickness of the polymer coating is in the range of about 5μm to about 20 μm.
 24. Biocompatible and biodegradable implant as inclaim 1, wherein said granules are fused together in a mold in apressurized CO₂ atmosphere under a pressure in a range of about 20 barto about 200 bar, for at least about 3 seconds.
 25. Biocompatible andbiodegradable implant as in claim 24, wherein the pressure is about 50bar.
 26. Biocompatible and biodegradable implant as in claim 24, whereinthe granules are under pressure for a range of about 3 seconds to about180 seconds.
 27. Biocompatible and biodegradable implant as in claim 1,wherein said granules are fused together by subjecting them within amold to a heat treatment at a temperature in a range of about 70° C. toabout 220° C. for at least about 10 seconds.
 28. Biocompatible andbiodegradable implant as in claim 27, wherein the temperature is in therange of about 75° C. to about 90° C.
 29. Biocompatible andbiodegradable implant as in claim 27, wherein the granules are heattreated for a range of about 10 seconds to about 5 minutes. 30.Biocompatible and biodegradable implant as in claim 1, wherein saidgranules are fused together in a mold in a pressurized CO₂ atmosphereunder a pressure in a range of about 20 bar to about 200 bar for atleast about 3 seconds, or said granules are fused together by subjectingthem within a mold to a heat treatment at a temperature in a range ofabout 70° C. to about 220° C. for at least about 10 seconds. 31.Biocompatible and biodegradable implant as in claim 1, wherein thegranules are entirely coated with the at least one biocompatible andbiodegradable layer of a polymer.